This document discusses preparing for sponsor audits of clinical trial sites. It explains that sponsors audit sites to ensure regulatory compliance, data integrity, and subject safety. The presentation covers why sponsors audit, what to expect during an audit, how to prepare, and how to respond to any observations or recommendations. The key points are to follow the protocol, document everything, make all necessary documents and staff available, be honest and transparent in responses, and see the audit as an opportunity for education rather than punishment.

1. Preparing for Sponsor Audits
Lorrie D. Divers, CCRP, RQAP-GCP
Director, Clinical Trials Quality Assurance
ACM Global Central Laboratory
RPCI Education Day for Clinical Research Staff
April 16, 2010 – Buffalo NY

2. Disclaimers
The contents of this presentation are my own
and do not represent the opinions or advice of
my employer, ACM Global Central Laboratory.
Information regarding FDA inspections
contained in this presentation was obtained from
publicly available sources. My interpretation of
this information is also my own.
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3. Preparing for Sponsor Audits
Follow the Protocol!
Comply with the Regulations!
Document Everything!
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4. Objectives
Why Do Sponsors Audit Investigators /
Study Sites?
What Should You Expect?
How to Prepare for a Sponsor Audit
How to Respond to Observations and
Recommendations
How to Be Prepared
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5. Why Sponsors Audit Sites
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6. Why Sponsors Audit Sites
Sponsors have a regulatory obligation to
monitor investigators / study sites
Auditing is a GCP best practice
Auditing is different than monitoring
Audits evaluate all study activities to
ensure
Protection of subjects’ rights
Integrity and reliability of the data generated
A well-controlled clinical trial was conducted
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7. Why Sponsors Audit Sites
Routine per Sponsor Procedures
Specific pre-defined criteria: New
investigators, data trends, study sites with
past issues, new monitor, etc.
Evaluate the monitoring, adequacy of
Sponsor procedures
Just good business / GCP practice
In preparation for FDA submission
It’s better to know sooner rather than later
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8. Why Sponsors Audit Sites
In anticipation of an FDA inspection
Prepare investigator and study site staff
Who? High enrollers, sites with significant
differences in comparison with others (AEs,
deviations, high response rate), new investigator /
study conducted was not the investigator’s specialty
For cause
Persistent non-compliance, suspected fraud, other
concerns expressed by monitor or sponsor staff
Observations from audit of in-house study files /
records and/or data
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9. What to Expect
Audits should provide education, not be
perceived as punishment
Generally two to three days in length
Agenda provided prior to audit, including list of
records and documents to be reviewed
Monitor may or may not attend
Auditor(s) may be Sponsor staff or may be
consultants
Suggestion: Ask for identification if not accompanied
by a monitor you know
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10. What to Expect
Auditors are not monitors
Primary concern is overall compliance
Regulations, GCP guidance / standards
Protocol and associated documents
Procedures – Yours and the Sponsors
What is revealed about the conduct of the
study?
Documents and records
Investigator, all study staff
Monitors, monitoring reports
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11. What to Expect
Auditors will talk to people and ask
questions, not just look at documents
Auditors will be looking at both the big
picture and the details
Questions about parts are used to evaluate
systems (parts = whole)
Questions about systems may reveal
concerns about parts (hole = missing parts)
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12. A few ‘secrets’ about Auditors
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13. A few ‘secrets’ about Auditors
Our Obsessive-Compulsive Disorder is
encouraged and may be pronounced
We will pull at threads and push against
boundaries
“What if…”
We will repeat ourselves
Frequently, on purpose, and often
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14. A few ‘secrets’ about Auditors
We are generally natural investigators
Skilled at formulating pictures from very few
puzzle pieces
Have had significant training and/or
experience with investigative techniques
Can read people
May be intentionally obtuse
May use the ‘Mr. Rogers’ approach or the ‘Dirty
Harry’ approach (or both)
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15. How to Prepare
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16. How to Prepare
Review the agenda and ensure all records and
all personnel will be available
Have a quiet location for the auditor(s) to work
Preferably empty of other records
Conference room is ideal
Most auditors will not want someone in
attendance at all times
Assign one person to interact regularly with auditor(s)
Agree upon frequency of checking in
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17. How to Prepare
Have all documentation related to the
study readily available
Regulatory binder
Exclude: Audit-related; financial/contractual
documents
Original signed informed consent forms
Case report forms
Source documentation
All charts, records, worksheets
Original or certified copies
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18. How to Prepare
If the study was conducted in the past, PI
and study staff should re-familiarize
themselves with the protocol and records
Additional documents to have available:
All clinical research related procedures and
operational documentation (standard forms,
checklists, etc.)
Training records for all study personnel
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19. During the Audit
Keep brief notes
Questions asked / answers given
Documents requested and provided
Discussions of complex issues
Keep copies of documents collected
Stamp or mark ‘copy’ and ‘confidential’ documents
collected by the auditor
Suggest a brief wrap-up at the end of each day
to confirm outstanding items, questions and any
requests for next day
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20. During the Audit
Respond to the question asked with simple,
honest, and complete answers
Listen actively and ask for clarification if you are
unsure of what is being asked
Don’t rely on memory alone – review the
documents yourself if necessary
‘I don’t know; we will review and get back to you by
the end of the day’ is an acceptable answer, if
appropriate
Deferring to and locating the correct person to answer
the question within a specified time frame is also
acceptable
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21. During the Audit
Don’t hide
Don’t just say ‘Yes’ when additional information is helpful
and relevant You may create the wrong picture
Don’t reveal
Don’t answer an unasked question It may lead to
unnecessary thread-pulling
Don’t debate
Clarify misunderstandings with positive rather than
negative statements
Be professional at all times
Auditors are always listening and observing
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22. At the End of the Audit
The auditor(s) should conduct an ‘exit interview’
Review observations and findings
May provide recommendations
Caution may be warranted
May review specific regulatory obligations
PI and key study staff should participate
There is no expectation of perfection
Clinical trials are conducted, monitored and audited
by human beings
Remember, it should be educational
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23. What Happens After the Audit
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24. What Happens After the Audit
Auditor and/or Sponsor should provide a
written report 3 – 6 weeks after the audit
Review and compare with your notes
Clarify any questions or concerns
Observations are most often rated as
Critical: An error that calls into question the reliability
and integrity of the data, presents significant risk(s)
to study subjects, indicates a lack of compliance with
GCP regulations. An accumulation of major errors
indicates a high level of suspicion for a systems
failure.
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25. An Auditor’s Perspective
Major: An error that suggests deficiencies in
compliance with GCP and/or the site’s
procedures but does not result in a critical error.
An accumulation of minor errors suggests a
systematic failure may have occurred.
Minor: An error that does not meet the definition
of critical or major but may suggest some
deficiencies in compliance.
May also include Recommendations
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26. Responding to Audit Findings
Will generally request a written response and/or
a corrective and preventive action plan (CAPA)
Your written responses should be SMART
Specific, Measurable, Attainable, Relevant, Time-
bound / Trackable
Be clear, be precise
Back up statements with facts (documents, data)
Try to avoid being defensive
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27. Responding to Audit Findings
Don’t promise actions you cannot, or do
not intend to, follow through on
If a corrective action cannot be carried out
right away, respond with a proposed
completion date
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28. Corrective & Preventive Action Plans
Corrective Actions = Reactive
Correct the source of non-compliance and
prevent future, similar problems
Start with root cause analysis (the ‘5 why’s’ of a
problem)
Then develop effective resolutions based on true
cause, such as:
SOPs – May need to be study specific
Checklists
Remedial training
Quality control checks
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29. Root Cause Investigation
When a mistake or an error or an incident
of non-compliance occurs, evaluate why
What was the actual mistake?
Hint: It may not be what it appears to be
Under what circumstances did it occur?
Who was involved?
When was the error detected and how?
What were the consequences?
Were subjects’ safety, rights or welfare impacted?
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30. CAPA
Preventive Actions = Proactive
Ensure quality and compliance the first time,
every time
SOPs
Checklists
Record keeping/actions as events occur
Training prior to duties
Good documentation practices
Frequent meetings and internal reviews
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31. How to Be Prepared
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32. How to Be Prepared
Know and understand regulations and
GCP guidance documents
http://www.fda.gov/ScienceResearch/Special
Topics/RunningClinicalTrials/default.htm
Investigator Responsibility – Protecting the Rights,
Safety, and Welfare of Study Subjects (FDA
Guidance, Oct. 2009)
Seek training
Reliable sessions can now be found on-line
Participate in national organizations’ meetings
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33. How to Be Prepared
Review the protocol and associated
documents
Consider how to conduct the study at your
site and in accordance with your procedures
Participate in investigator meetings, SIVs
Learn from monitoring visits and audits
Ask questions
Apply the concept of Quality Systems
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34. Being Prepared Avoids…
In both 2000 and 2004, the most common
observations cited by FDA inspectors
Failure to follow the protocol / investigational
plan
Failure to maintain adequate and accurate
records
Failure to account for disposition of study
drugs / test articles
Failure to report Adverse Events
Problems related to informed consent
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35. Being Prepared & Quality Systems
“Janet Woodcock, the Deputy Commissioner of
Operations at the FDA, stated that she is
strongly encouraging all parties conducting
clinical research to recognize that quality is a
‘system’ characteristic and that quality cannot
be inspected into a trial but instead must be
designed into the process.”
Kit Howard, A Risk-Based Approach for Assessing Data
Quality, Journal of Clinical Research Vol. 3, No. 6, June 2007
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36. Quality Systems
A comprehensive approach that
Complies with regulations and GCP
Assures control and integrity of data, protection of
subjects’ rights and welfare
Standardizes processes to minimize unintended
variability and diminish risk
Measures quality at each critical step
“Quality system means the organizational structure,
responsibilities, procedures, processes, and resources
for implementing quality management.” 21 CFR 820.3(v)
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37. An FDA Inspection Perspective
“This letter also discusses your written response
dated February 23, 2005, to the inspectional
observations noted on the Form FDA 483. While
the submission provides an explanation of events
that occurred at your site, it does not discuss how
you personally intend to address the deficiencies,
nor does it provide a detailed explanation of system-
wide corrective actions that will be take to prevent
these deficiencies from occurring in the future. It is
recommended, at a minimum, that staff training be
provided that includes retraining on Good Clinical
Practices (GCP) guideline with emphasis on safety.
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38. An FDA Inspection Perspective
This will assist you and your staff in the protection of
human subjects as it relates to the informed consent
process and the federal regulations for
investigational device exemption studies. In
addition, we recommend that you establish specific
Standard Operating Procedures (SOPs) for your
research activities.”
Source: FDA Warning letter, Jun 23, 2005; Khoury
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39. Unfortunately, “no magic formula”
“Currently, some individuals suggest using
a quality system approach to avoid
compliance actions, improve research
data quality and facilitate the advance of
new technologies into the marketplace.
Unfortunately, there is no magic formula
for how to devise or implement a quality
system in the clinical trial setting…..”
ME Marcarelli, ‘5 Habits of Highly Effective Sponsors’
Regulatory Affairs Focus, April 2007
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40. 7 Elements of a Quality System
Equipment and Facility controls
Records, Documents, Change Controls
Material Controls
i.e., Investigational product(s) and ancillary
supplies
Design Controls
i.e., Key study design elements such as subject
screening/selection, AE reporting, laboratory or
other special testing
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41. 7 Elements of a Quality System
Production & Process Controls
i.e., Study personnel, PI role and
responsibilities, monitoring
Management Controls
i.e., Procedures, policies, structure
Corrective and Preventive Actions
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42. A Quality Systems Approach
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43. A Quality Systems Approach
Failure to follow the protocol /
investigational plan
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44. A Quality Systems Approach
Principal Investigator should personally conduct
/ supervise the conduct of the clinical trial
A PI can delegate authority but cannot delegate
responsibility for clinical trials
Read the protocol, IB, other documents related to the
conduct of the study provided by the sponsor
PI should keep himself/herself informed throughout
the conduct of the study
Meet with sub-investigators, study staff
Read IRB and sponsor correspondence
Make time to meet with the monitor
Provide training opportunities for self and study staff
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45. A Quality Systems Approach
PI should ensure staff (and self) are adequately
trained on / understand delegated tasks (and
responsibilities)
Protocol procedures
Regulatory commitments
Investigational product accountability
Informed consent process
Good documentation practices
Document training
If needed, request protocol-specific training from sponsor
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46. A Quality Systems Approach
Sites should develop and use standard
operating procedures (SOPs) to ensure
accuracy and consistency
Checklists, forms, process flowcharts
Create and use accurate eligibility, study
procedure, reminder checklists
Inclusion and exclusion criteria exist to protect
subjects and ensure scientific validity of the results,
thus protecting future recipients of the product
Adhere to all the other protocol, sponsor, IRB and
institutional requirements
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47. An Auditor’s Perspective
Auditors will be sensitive to warning signs of lack
of PI involvement, over-delegation or delegation
to non-qualified personnel
No source notes with PI signature
Never available to meet with monitor
Not initialing/dating IRB and/or sponsor
correspondence
No evidence of assessment of AEs or SAEs,
inclusion/exclusion, study procedure results, informed
consent process
Study staff express frustration with investigator
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48. A Quality Systems Approach
Failure to maintain adequate and accurate
records
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49. A Quality Systems Approach
Document, document, document
Less is not “better”
Standard of care PLUS protocol required
information
If it’s a document related to the study,
keep it!
Don’t throw it out, shred it, misplace it, put it in a pile,
stuff it in a drawer, leave it at home, let the kids use it
for scrap paper, keep it in the trunk of the car….
Maintain a date-ordered, topic-ordered file, preferably in a
study-specific binder
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50. A Quality Systems Approach
Keep CRFs up to date to ensure accurate
information is recorded and maintained
Use a quality control process to ensure
IRB approval is in place prior to enrolling
subjects
Examples: Checklist; internal study start-up
meeting with all sub-investigators and study
staff
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51. A Quality Systems Approach
Make sure you are aware of, and
understand, your IRB’s policies and
practices
How do they issue approvals; is the ICF
stamped or watermarked?
Complete the continuing review report
accurately and in a timely manner
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52. A Quality Systems Approach
A simple information log / spreadsheet for
IRB submissions and documents can be
used to track:
Date of initial IRB approval
Documents approved
Expected date(s) of continuing review
report(s)
Date of re-approval(s)
Version/approval date(s) of updated ICFs
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53. Documentation > Documents
How the paper tells the story is important
Inaccurate or incomplete records
Late entries
Improper corrections
Inappropriate personnel completing
Electronic records
21 CFR Part 11
FDA Guidance: Computerized Systems Used
In Clinical Investigations, May 2007
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54. ALCOA Principles for GDP
Attributable: Appropriately signed, initialed,
dated, (who wrote it when)
Legible: No hieroglyphics; properly corrected
One line through, add new information, initial
and date
Contemporaneous: Documented in proximity
to occurrence, not 6 months later
Original: If not, why not? Certified copies
Accurate: Correct subject; sensible dates;
modifications clearly explained if not self-evident
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55. And now a few words about…
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56. Notes to File
From ‘Note to Self: No More Notes to File’
by Carl Anderson, Applied Clinical Trials,
March 2008
“A common document at many clinical sites is
the memo or note to file (NTF). When used
properly, an NTF can be a positive
practice. Some in the clinical trials
community, however, seem to think an NTF is
a panacea for all things that have gone
wrong. Make a mistake? Then write an
NTF…”
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57. Notes to File
Retrospective “documentation” is a very
risky practice for both sponsors and sites
From a Warning Letter issued to Sanofi-
Aventis in October, 2007
“Our investigation found that Aventis failed to
take any action to secure compliance while the
study was ongoing except to generate
numerous memos to file after all subjects had
completed the study.”
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58. Notes to File
From a Warning Letter issued to a clinical
investigator
“We note that there were no medical histories in these
subjects’ research files. For subjects [-] you created
Memos to File stating that medical records were not
obtained due to subjects’ primary care physicians
being located in Mexico. These memos do not
sufficiently address the issue of the missing
medical histories. Without the medical histories…it
is not possible to verify if the subjects met inclusion
criteria for the study.” [Source: June 30, 2008; Hsueh]
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59. An Auditor’s Perspective
Notes to file are “flags” for auditors and
regulatory authority inspectors
Prompt us to look at processes and
procedures related to the issue documented
Prompt us to ask more specific questions
Tell us a “story” about the conduct of the
study, including about the monitoring
So, how do you want your NTFs to look?
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60. Do you want…
NTFs that just document errors without
Examining the cause of the problem
Explaining the remediation
Being necessary
Notes to file that are
Poorly and/or inaccurately written
Frequent and repetitive
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61. Do you want…
Effective notes to file that correct, clarify, or add
to the existing source documentation and are
Well-written – clear and accurate
Relevant – appropriate level of detail
Infrequent – and not repetitive
Timely – not written the day before an audit or
inspection
NTFs that demonstrate GCP compliance by
documenting corrective and preventive actions
(CAPA)
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62. An Auditor’s Perspective
Good Documentation Practices prevent the
need for retrospective Notes to File
Examples of how poor practices lead to this
“Late entries are sometimes made without adequate
documentation by the person making the entry including the
time and date the entry was made. In addition, the actual
source of the late entry is not always evident. This is
particularly evident with regards to AEs.”
“Progress notes occasionally had multiple date stamps, or
were undated, making it difficult to determine the date the
exam was actually performed. In addition, some of the date
changes are not dated or initialed and it cannot be
determined when or by whom these changes were made.”
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63. A Quality Systems Approach
Failure to account for disposition of study
drugs / test articles
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64. A Quality Systems Approach
Maintain prospective accountability records
Use the sponsor-provided form, if possible
Keep all shipping receipts and return records
Check the protocol and/or request written information
from the sponsor on accountability
Periodically reconcile against stock and against
patient administration/use records
Resolve and document any discrepancies at the
time they occur or as soon as discovered
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65. A Quality Systems Approach
Review the protocol’s randomization (or
treatment assignment) requirements
Ensure all staff understand and are aware
If it is an oral medication the study subject
will be taking at home, determine how
treatment compliance will be documented
Diary card, PDA, IVRS, daily phone log
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66. A Quality Systems Approach
Failure to report Adverse Events
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67. A Quality Systems Approach
Understand the protocol, sponsor, and IRB
requirements for reporting adverse events,
serious adverse events, and safety
updates
Medically qualified study staff (investigator
or sub-investigator) should document
assessment of all adverse events
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68. A Quality Systems Approach
Use a dated cover letter when submitting
information to the IRB and maintain a copy
with the submitted information
A simple tracking spreadsheet can also be
helpful
Date SAE or safety report was submitted
Description / identification of what was
submitted, when, to whom (IRB, Sponsor,
others)
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69. A more few words about…
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70. Source / Study Worksheets
Source documentation is a regulatory
responsibility of clinical investigators
Can delegate authority but not responsibility
Delegation of authority log with printed name,
signature, initials, roles, date(s) involved
Appropriately trained, qualified and
supervised personnel
No appearance of falsification or fraud
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71. Sponsor’s Expectations
FDA Guideline for the Monitoring of
Clinical Investigations, January 1988
“A sponsor is responsible for assuring that
data submitted to FDA in support of safety
and effectiveness of a test article are accurate
and complete. The most effective way to
assure the accuracy of data submitted to FDA
is to review individual subject records and
other supporting documents and compare
those records with the reports prepared by the
investigator for submission to the sponsor.”
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72. Source Data Verification
“All information in original records and certified
copies of original records of clinical findings,
observations, or other activities in a clinical trial
necessary for the reconstruction and evaluation
of the trial.” [ICH E6, 1.51]
FDA has consistently advised that source record
quality is enhanced by using the site’s normal
record keeping system to the maximum extent
possible
See for example, “The Facts About Source Documents,”
www.fda.gov/Cder/present/dia-699/wollen-dia99/wollen-dia99.ppt)
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73. Normal Records vs. Source Worksheets
What are your routine records? Are they
adequate and accurate?
Source worksheets should supplement,
not substitute for or duplicate records
Normal clinical documentation ≠ clinical
research record-keeping but if normal
documentation is adequate for the protocol,
using different documentation is risky
And what if there are only source
worksheets?
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74. An Auditor’s Perspective
An Example
“Recommendation: The site should reconsider their use of
sponsor-provided source worksheets in situations where their
routine clinic documentation is adequate. They should not
duplicate information but should use the source worksheets
only to document information not captured as part of their
normal record-keeping. One recommendation is to cross-out
unnecessary portions of source worksheets, indicating “see
clinic chart,” and fill out only study-specific questions /
information not otherwise adequately documented in the clinic
and/or surgery records. In addition, if source worksheets are
used, they must be signed like a clinic chart note would be.”
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75. A Quality Systems Approach
Problems related to informed consent
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76. A Quality Systems Approach
Learn the history of the ethics of clinical
research
On-line courses are available from the NCI and NIH
A number of good reference books are available
Check with your IRB, ask the sponsor
Read the regulations
Ethical obligations became regulatory obligations and
regulatory obligations are the LAW
Numerous guidance documents aid in understanding
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77. A Quality Systems Approach
Adequacy of informed consent is an
investigator responsibility
Carefully review any sponsor-provided ICF
template
Compare it to the protocol, the product information,
and your IRB requirements
Persons obtaining consent should be
appropriately qualified / trained to do so
If not done by PI or medically qualified sub-
investigator, subject should have opportunity to
discuss any questions or concerns
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78. A Quality Systems Approach
Establish and follow good document
control practices for ICFs
If your IRB does not stamp or watermark the
IRB-approved consent form, ask them to
consider this or do it yourself (SOP)
Password-protect / limit access to any non-
approved versions that may be stored on the
computer
Use a tracking and/or filing method to ensure
only the current IRB-approved version is
used
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79. A Quality Systems Approach
The form is just a document - Informed
consent is a process
Auditors look for evidence of the process
ICF version used consistent with IRB approved
version? How is this ensured?
Who obtained consent? Were all questions
addressed?
Was consent obtained prior to any protocol-
specific procedures?
How was re-consent carried out and documented?
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80. An Auditor’s Perspective
Informed Consent process issues are often
illustrated by a pattern of errors
“A significant number of signed Consent Forms have
date and signature anomalies made both by subjects
and study personnel.”
Date(s) changed – In several instances, changed by several
days, weeks, or in one case, by more than a month
Two instances of subject signing on ‘Person obtaining
consent line’ – One instance remained uncorrected
Often not dated by subject and/or PI themselves
“For multiple subjects, the incorrect version of the ICF
was used initially, and re-consent with the correct
version not obtained, until observed by the monitor.”
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81. What Can You Do?
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82. The Paper Tells the Story
Documentation is how auditors determine how
the study was conducted
Help them just turn the pages….
Accurate, complete documentation of all aspects
of the study illustrates regulatory and protocol
compliance
Subject records
IRB records
Drug or device accountability
Informed consent
AE / SAE reporting
Correspondence
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83. The Paper Tells the Story
Correction is a documented action
Appropriate to the cause of the problem
Procedures, checklists, templates, etc.
Training
Quality control checks
Compliance is a behavior exhibited by
Documentation
Knowledge of regulations
Execution of procedures
Audits
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84. What Can You Do
Practice good documentation practices from the
start of the study (ALCOA)
Document errors and their correction in a timely
manner
Recognize patterns and consider the story they tell
Make CAPA a habit, including assessing
effectiveness
Understand the protocol, GCP requirements
and investigator responsibilities
Ask questions of the monitor, sponsor, PI, IRB,
auditors
Checkout the FDA, NIH and NCI websites
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85. What Can You Do
Remember the key areas of GCP compliance
Subject welfare
Data validity and integrity
Test article (study drug, investigational device) control
Ignorance of the regulations (law) is not an excuse
Remember the keys to quality
Effective and adequate the first time = the best
way every time
If it isn’t documented….
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86. Questions
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87. Contact Information
Lorrie D. Divers, CCRP, RQAP-GCP
585-429-2386
LDivers@acmgloballab.com
“Quality is never an accident; it is always the
result of high intention, sincere effort, intelligent
direction and skillful execution; it represents the
wise choice of many alternatives.”
Willa A. Foster
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